The Hedgehog (Hh) pathway plays a critical role in the patterning, homeostasis, and oncogenic transformation of multiple tissues. For example, Hh signaling regulates cerebellar patterning and growth, and Hh pathway activation is a leading cause of medulloblastoma, the most common pediatric brain cancer. Genetic screens have revealed a number of Hh pathway regulators, including canonical signaling proteins that are conserved across metazoans and vertebrate-specific modulators. These studies have provided a general framework for vertebrate Hh signal transduction, which in mammals is initiated by the binding of secreted polypeptides (Sonic, Shh; Indian, Ihh; or Desert, Dhh) to the 12-transmembrane receptor Patched1 (Ptch1) and the subsequent activation of Smoothened (Smo), a G protein-coupled receptor-like protein. Smo then acts through unknown mechanisms to control the functions of Gli2 and Gli3, zinc finger transcription factors that exist as a balance between N-terminal repressors (Gli2/3R), full-length proteins (Gli2/3FL), or phosphorylated forms of Gli2/3FL that are transcriptionally active (Gli2/3A). This process is mediated at least in part by Suppressor of Fused (Sufu), a direct negative regulator of Gli function. The primary cilium serves as a Hh pathway nexus; Ptch1, Smo, Sufu, Gli2, and Gli3 traffic through the cilium in a pathway activity-dependent manner, and many of their interactions appear to occur within or depend upon this microtubule-scaffolded structure. Upon Hh pathway activation, Gli2A and to a lesser extent Gli3A then drive the transcription of Hh target genes, including Ptch1 and the constitutively active factor Gli1.
The therapeutic utility of Hh pathway inhibitors has been confirmed by the recent approval of vismodegib (ERIVEDGE™) by the U.S. Food and Drug Administration. It is currently indicated for patients with basal cell carcinoma. Vismodegib is also undergoing clinical trials for metastatic colorectal cancer, small-cell lung cancer, advanced stomach cancer, pancreatic cancer, chondrosarcoma and medulloblastoma. Vismodegib acts as an antagonist of the Smoothened receptor (SMO). SMO inhibition causes the transcription factors GLI1 and GLI2 to remain inactive, which prevents the expression of tumor-mediating genes within the Hedgehog pathway. This pathway is pathogenetically relevant in more than 90% of basal cell carcinomas.
Current SMO-targeting therapies, despite their promise, have some potential drawbacks. Hh signaling is an important regulator of bone growth in juvenile mice, and Smo inhibitors cause permanent dwarfism in animal models. While such pharmacological side effects may be outweighed by the pernicious nature of certain Hh pathway-induced cancers, the side effects may warrant contraindication in other cases. New Hh pathway inhibitors, including those that act through different mechanisms, are needed to address these challenges.
In addition to their potential utility in treating tumors, small-molecule inhibitors of the Hh pathway can be valuable tools for studying Hh signaling mechanisms.